Irmgard Tegeder

Cyclooxygenase-independent actions of cyclooxygenase inhibitors

Several studies have demonstrated unequivocally that certain nonsteroidal anti‐inflammatory drugs (NSAIDs) such as sodium salicylate, sulindac, ibuprofen, and flurbiprofen cause anti‐inflammatory and antiproliferative effects independent of cyclooxy‐genase activity and prostaglandin synthesis inhibition. These effects are mediated through inhibition of certain transcription factors such as NF‐κB and AP‐1. The respective NSAIDs might interfere directly with the transcription factors, but their effects are probably mediated predominantly through alterations of the activity of cellular kinases such as IKKß, Erk, p38 MAPK, or Cdks. These effects apparently are not shared by all NSAIDs, since indomethacin failed to inhibit NF‐κB and AP‐1 activation as well as Erk and Cdk activity. In contrast, indomethacin was able to activate PPARγ, which was not affected by sodium salicylate or aspirin. The differences in cyclooxygenase‐independent mechanisms may have consequences for the specific use of these drugs in individual patients because additional effects may either enhance the efficacy or reduce the toxicity of the respective compounds.—Tegeder, I., Pfeilschifter, J., Geisslinger, G. Cyclooxygenase‐independent actions of cyclooxygenase inhibitors FASEB J. 15, 2057–2072 (2001)

GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.

We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury–evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.

COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib

The regular use of various nonsteroidal anti‐inflammatory drugs (NSAIDs) was shown to decrease the incidence of colorectal cancer. This effect is thought to be caused predominantly by inhibition of cyclooxygenase‐2 (COX‐2) and, subsequently, prostaglandin synthesis. However, recent studies have suggested that COX‐independent pathways may contribute considerably to these antiproliferative effects. To evaluate the involvement of COX‐dependent and COX‐independent mechanisms further, we assessed the effects of celecoxib (selective COX‐2 inhibitor) and SC560 (selective COX‐1 inhibitor) on cell survival, cell cycle distribution, and apoptosis in three colon cancer cell lines, which differ in their expression of COX‐2. Both drugs induced a G0/G1 phase block and reduced cell survival independent of whether or not the cells expressed COX‐2. Celecoxib was more potent than SC560. The G0/G1 block caused by celecoxib could be attributed to a decreased expression of cyclin A, cyclin B1, and cyclin‐dependent kinase‐1 and an increased expression of the cell cycle inhibitory proteins p21Waf1 and p27Kip1. In addition, celecoxib, but not SC560, induced apoptosis, which was also independent of the COX‐2 expression of the cells. In vivo, celecoxib as well as SC560 reduced the proliferation of HCT‐15 (COX‐2 deficient) colon cancer xenografts in nude mice, but both substances had no significant effect on HT‐29 tumors, which express COX‐2 constitutively. Thus, our in vitro and in vivo data indicate that the antitumor effects of celecoxib probably are mediated through COX‐2 independent mechanisms and are not restricted to COX‐2 over‐expressing tumors.

Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors

Although endocannabinoids constitute one of the first lines of defense against pain, the anatomical locus and the precise receptor mechanisms underlying cannabinergic modulation of pain are uncertain. Clinical exploitation of the system is severely hindered by the cognitive deficits, memory impairment, motor disturbances and psychotropic effects resulting from the central actions of cannabinoids. We deleted the type 1 cannabinoid receptor (CB1) specifically in nociceptive neurons localized in the peripheral nervous system of mice, preserving its expression in the CNS, and analyzed these genetically modified mice in preclinical models of inflammatory and neuropathic pain. The nociceptor-specific loss of CB1 substantially reduced the analgesia produced by local and systemic, but not intrathecal, delivery of cannabinoids. We conclude that the contribution of CB1-type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount, which should enable the development of peripherally acting CB1 analgesic agonists without any central side effects.

Pharmacokinetics of Opioids in Liver Disease

The liver is the major site of biotransformation for most opioids. Thus, the disposition of these drugs may be affected in patients with liver insufficiency. The major metabolic pathway for most opioids is oxidation. The exceptions are morphine and buprenorphine, which primarily undergo glucuronidation, and remifentanil, which is cleared by ester hydrolysis.Oxidation of opioids is reduced in patients with hepatic cirrhosis, resulting in decreased drug clearance [for pethidine (meperidine), dextropropoxyphene, pentazocine, tramadol and alfentanil] and/or increased oral bioavailability caused by a reduced first-pass metabolism (for pethidine, dextropropoxyphene, pentazocine and dihydrocodeine). Although glucuronidation is thought to be less affected in liver cirrhosis, the clearance of morphine was found to be decreased and oral bioavailability increased.The consequence of reduced drug metabolism is the risk of accumulation in the body, especially with repeated administration. Lower doses or longer administration intervals should be used to remedy this risk. Special risks are known for pethidine, with the potential for the accumulation of norpethidine, a metabolite that can cause seizures, and for dextropropoxyphene, for which several cases of hepatotoxicity have been reported. On the other hand, the analgesic activity of codeine and tilidine depends on transformation into the active metabolites, morphine and nortilidine, respectively. If metabolism is decreased in patients with chronic liver disease, the analgesic action of these drugs may be compromised. Finally, the disposition of a few opioids, such as fentanyl, sufentanil and remifentanil, appears to be unaffected in liver disease.

Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications

Opioids are powerful analgesics but also drugs of abuse. Because opioid addicts are susceptible to certain infections, opioids have been suspected to suppress the immune response. This was supported by the finding that various immune-competent cells express opioid receptors and undergo apoptosis when treated with opioid alkaloids. Recent evidence suggests that opioids may also effect neuronal survival and proliferation or migrating properties of tumor cells. A multitude of signaling pathways has been suggested to be involved in these extra-analgesic effects of opioids. Growth-promoting effects were found to be mediated through Akt and Erk signaling cascades. Death-promoting effects have been ascribed to inhibition of nuclear factor-κB, increase of Fas expression, p53 stabilization, cytokine and chemokine release, and activation of nitric oxide synthase, p38, and c-Jun-N-terminal kinase. Some of the observed effects were inhibited with opioid receptor antagonists or pertussis toxin; others were unaffected. It is still unclear whether these properties are mediated through typical opioid receptor activation and inhibitory G-protein-signaling. The present review tries to unravel controversial findings and provides a hypothesis that may help to integrate diverse results.

Celecoxib loses its anti-inflammatory efficacy at high doses through activation of NF-κB

Celecoxib, a selective cyclooxygenase‐2 (COX‐2) inhibitor, has recently been approved for the symptomatic treatment of arthritis. In some clinical studies, doses of 400 and 800 mg/day provided somewhat less efficacy compared with 200 mg/day, which suggests an early ceiling effect. Using the zymosan‐induced inflammation model in rats, we show that celecoxib significantly reduces paw swelling at 50 mg/kg but completely loses its anti‐inflammatory efficacy at doses ≥100 mg/kg. To evaluate the underlying mechanisms, we used rat renal mesangial cells as a cell culture model. In these cells, celecoxib (50 μM) increased the interleukin Iβ stimulated nuclear translocation and DNA binding of NF‐κB and facilitated the degradation of I‐κB. Consequently, COX‐2 and tumor necrosis factor α (TNF‐α) expression were increased. The up‐regulation of COX‐2 and TNF‐α also occurred in the spinal cord of rats treated with celecoxib (≥100 mg/kg), indicating that in vitro mechanisms were relevant in vivo. Clinically, the overexpression of COX‐2 might be less important because celecoxib inhibits COX‐2 enzymatically. However, the up‐regulation of TNF‐α and possibly other NF‐κB regulated proinflammatory genes might worsen the pathophysiological processes underlying chronic arthritis.

No NO, no pain? The role of nitric oxide and cGMP in spinal pain processing

A large body of evidence indicates that nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) essentially contribute to the processing of nociceptive signals in the spinal cord. Many animal studies have unanimously shown that inhibition of NO or cGMP synthesis can considerably reduce both inflammatory and neuropathic pain. However, experiments with NO donors and cGMP analogs also caused conflicting results because dual pronociceptive and antinociceptive effects of these molecules have been observed. Here, we summarize the most recent advances in the understanding of NO- and cGMP-dependent signaling pathways in the spinal cord and further unravel the role of NO and cGMP in pain processing.

Incidence and costs of adverse drug reactions during hospitalisation: computerised monitoring versus stimulated spontaneous reporting.

AbstractObjective: To implement a computer-based adverse drug reaction monitoring system and compare its results with those of stimulated spontaneous reporting, and to assess the excess lengths of stay and costs of patients with verified adverse drug reactions. Design: A prospective cohort study was used to assess the efficacy of computer-based monitoring, and case-matching was used to assess excess length of stay and costs. Setting: This was a study of all patients admitted to a medical ward of a university hospital in Germany between June and December 1997. Patients and participants: 379 patients were included, most of whom had infectious, gastrointestinal or liver diseases, or sleep apnoea syndrome. Patients admitted because of adverse drug reactions were excluded. Methods: All automatically generated laboratory signals and reports were evaluated by a team consisting of a clinical pharmacologist, a clinician and a pharmacist for their likelihood of being an adverse drug reaction. They were classified by severity and causality. For verified adverse drug reactions, control patients with similar primary diagnosis, age, gender and time of admission but without adverse drug reactions were matched to the cases in order to assess the excess length of hospitalisation caused by an adverse drug reaction. Results: Adverse drug reactions were detected in 12% of patients by the computer-based monitoring system and stimulated spontaneous reporting together (46 adverse reactions in 45 patients) during 1718 treatment days. Computer-based monitoring identified adverse drug reactions in 34 cases, and stimulated spontaneous reporting in 17 cases. Only 5 adverse drug reactions were detected by both methods. The relative sensitivity of computer-based monitoring was 74% (relative specificity 75%), and that of stimulated spontaneous reporting was 37% (relative specificity 98%). All 3 serious adverse drug reactions were detected by computer-based monitoring, but only 2 out of the 3 were detected by stimulated spontaneous reporting. The percentage of automatically generated laboratory signals associated with an adverse drug reaction (positive predictive value) was 13%. The mean excess length of stay was 3.5 days per adverse drug reaction. 48% of adverse reactions were predictable and detected solely by computer-based monitoring. Therefore, the potential for savings on this ward from the introduction of computer-based monitoring can be calculated as EUR56 200/year (

Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation.

US59 600/year) [1999 values]. Conclusion: Computer monitoring is an effective method for improving the detection of adverse drug reactions in inpatients. The excess length of stay and costs caused by adverse drug reactions are substantial and might be considerably reduced by earlier detection.